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Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases

Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)...

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Autores principales: Cheng, Xiaoyi, Barakat, Radwa, Pavani, Giulia, Usha, Masuma Khatun, Calderon, Rodolfo, Snella, Elizabeth, Gorden, Abigail, Zhang, Yudi, Gadue, Paul, French, Deborah L., Dorman, Karin S., Fidanza, Antonella, Campbell, Clyde A., Espin-Palazon, Raquel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667254/
https://www.ncbi.nlm.nih.gov/pubmed/37996457
http://dx.doi.org/10.1038/s41467-023-43349-1
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author Cheng, Xiaoyi
Barakat, Radwa
Pavani, Giulia
Usha, Masuma Khatun
Calderon, Rodolfo
Snella, Elizabeth
Gorden, Abigail
Zhang, Yudi
Gadue, Paul
French, Deborah L.
Dorman, Karin S.
Fidanza, Antonella
Campbell, Clyde A.
Espin-Palazon, Raquel
author_facet Cheng, Xiaoyi
Barakat, Radwa
Pavani, Giulia
Usha, Masuma Khatun
Calderon, Rodolfo
Snella, Elizabeth
Gorden, Abigail
Zhang, Yudi
Gadue, Paul
French, Deborah L.
Dorman, Karin S.
Fidanza, Antonella
Campbell, Clyde A.
Espin-Palazon, Raquel
author_sort Cheng, Xiaoyi
collection PubMed
description Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)-derived HSPCs and their derivatives has been elusive, necessitating a better understanding of the developmental mechanisms that trigger HSPC specification. Here, we reveal that early activation of the Nod1-Ripk2-NF-kB inflammatory pathway in endothelial cells (ECs) primes them to switch fate towards definitive hemogenic endothelium, a pre-requisite to specify HSPCs. Our genetic and chemical embryonic models show that HSPCs fail to specify in the absence of Nod1 and its downstream kinase Ripk2 due to a failure on hemogenic endothelial (HE) programming, and that small Rho GTPases coordinate the activation of this pathway. Manipulation of NOD1 in a human system of definitive hematopoietic differentiation indicates functional conservation. This work establishes the RAC1-NOD1-RIPK2-NF-kB axis as a critical intrinsic inductor that primes ECs prior to HE fate switch and HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs and their derivatives for the treatment of blood disorders.
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spelling pubmed-106672542023-11-23 Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases Cheng, Xiaoyi Barakat, Radwa Pavani, Giulia Usha, Masuma Khatun Calderon, Rodolfo Snella, Elizabeth Gorden, Abigail Zhang, Yudi Gadue, Paul French, Deborah L. Dorman, Karin S. Fidanza, Antonella Campbell, Clyde A. Espin-Palazon, Raquel Nat Commun Article Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)-derived HSPCs and their derivatives has been elusive, necessitating a better understanding of the developmental mechanisms that trigger HSPC specification. Here, we reveal that early activation of the Nod1-Ripk2-NF-kB inflammatory pathway in endothelial cells (ECs) primes them to switch fate towards definitive hemogenic endothelium, a pre-requisite to specify HSPCs. Our genetic and chemical embryonic models show that HSPCs fail to specify in the absence of Nod1 and its downstream kinase Ripk2 due to a failure on hemogenic endothelial (HE) programming, and that small Rho GTPases coordinate the activation of this pathway. Manipulation of NOD1 in a human system of definitive hematopoietic differentiation indicates functional conservation. This work establishes the RAC1-NOD1-RIPK2-NF-kB axis as a critical intrinsic inductor that primes ECs prior to HE fate switch and HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs and their derivatives for the treatment of blood disorders. Nature Publishing Group UK 2023-11-23 /pmc/articles/PMC10667254/ /pubmed/37996457 http://dx.doi.org/10.1038/s41467-023-43349-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cheng, Xiaoyi
Barakat, Radwa
Pavani, Giulia
Usha, Masuma Khatun
Calderon, Rodolfo
Snella, Elizabeth
Gorden, Abigail
Zhang, Yudi
Gadue, Paul
French, Deborah L.
Dorman, Karin S.
Fidanza, Antonella
Campbell, Clyde A.
Espin-Palazon, Raquel
Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
title Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
title_full Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
title_fullStr Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
title_full_unstemmed Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
title_short Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
title_sort nod1-dependent nf-kb activation initiates hematopoietic stem cell specification in response to small rho gtpases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667254/
https://www.ncbi.nlm.nih.gov/pubmed/37996457
http://dx.doi.org/10.1038/s41467-023-43349-1
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